1. Field of the Invention
The present invention relates to compounds for maintaining the vascular function to treat or prevent the ischemic and metabolic diseases, more particularly to aporphine and oxoaporphine compounds that can be used to preserve the vascular endothelial function to prevent or treat ischemic and metabolic diseases.
2. Background of the Invention
With the progress of society and the advance in sciences and technology, life expectancy gradually increases. Many people now suffer from various diseases due to old age, diet, obesity, lack of exercise or living under stress. Among these diseases, ischemic diseases are among the main causes of death and physical impairment. Ischemic and metabolic diseases have a major impact and cause substantial loss to people, family, society and the state. Therefore, it is important to find agents to prevent the ischemic and metabolic diseases.
Among ischemic diseases, vascular damage, particularly endothelial dysfunction is a major abnormality presented in varying degrees at different stages. The endothelial layer in vessels provides a critical interface between the elements of blood and tissues. A healthy endothelial layer provides a smooth, quiescent surface that limits the activation of clotting and proinflammatory factors, blocks the transfer of atherogenic lipid particles into the arterial wall, and prevents adhesion of platelets and monocytes to the vascular endothelials. Vascular endothelial dysfunction, therefore, may occur at any or all levels in the arterial system and may contribute to the development and progression of atherosclerosis by favoring coagulation, cell adhesion and inflammation, by promoting inappropriate vasoconstriction and/or vasodilatation, and by enhancing transendothelial transport of atherogenic lipoproteins. Atherosclerosis may lead to the development of cardiac or cerebral diseases even though atherosclerosis occurs in the coronary or intracranial arteries.
Vascular dysfunction also plays a role in the progression of metabolic diseases, because coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, which occur with increased frequency in individuals with hypertension hyperlipidemia, obesity, diabetes and renal disease. A number of cardiovascular risk factors, including coronary artery disease, hypertension, hypertriglyceridemia and visceral obesity have been collectively termed the metabolic syndrome. The metabolic syndrome is typically associated with endothelial dysfunction and insulin resistance, which is the major characteristic of Type II diabetes. Endothelial dysfunction contributes to impaired insulin action by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolic active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemo attractants and cytokines worsens the insulin resistance and endothelial dysfunction.
There have been many studies focused on the endothelial function to prevent the vascular endothelial damage. The role of nitric oxide (NO), a vasodilator synthesized by endothelial nitric oxide synthase (eNOS), has been extensively studied in recent years. Many studies indicated that various drugs with different mechanisms for the management of cardiovascular and metabolic diseases, such as statins, PDE5 inhibitors, ACE inhibitors, may limit ischemic or ischemia-reperfusion injuries by enhancing NO or eNOS activity. (Journal of Molecular and Cellular Cardiology, 2006, 40(1), 16-23.) The abnormalities of nitric oxide (NO) release and endothelial nitric oxide synthase (eNOS) system have been shown to provide the link between insulin resistance and endothelial dysfunction. (Diabetes/Metabolism Research and Reviews, Feb. 28, 2006.) Therefore, compounds capable of maintaining or increasing endothelial nitric oxide synthase (eNOS) activities, should preserve vascular endothelial functions and can be used not only to prevent the ischemic diseases, but also to improve the insulin resistance to activate the glucose utility in tissues, leading to lowered blood sugar level. It is desirable to have compounds that can be used in the prevention and treatment of vascular dysfunction resulting in ischemic and metabolic diseases.